goal in mind: to improve outcomes for our patients by integrating precision medicine approaches as an addition the standard of care. Led by world renown genomics experts Drs. Richard Wilson and Elaine Mardis, the Steve and Cindy Rasmussen Institute for Genomic Medicine. is at the forefront of genomic medicine and translation. From a programmatic standpoint, all patients with rare and refractory disease are nominated onto the Cancer protocol. Here tumor tissue and matching normal control blood samples may undergo germline analyses in addition to whole exome and RNA sequencing along with methylation profiling. The resulting data is reviewed in concert with the clinical course for each patient during
which limits the adaptive immune system’s ability to fight the tumor. Numerous studies and therapeutic strategies are now emerging to selectively deplete or reprogram myeloid cells in cancer. These cellular based strategies and tumor extrinsic approaches in addition to genomic medicine will define the next iteration of precision medicine. It is this next iteration that should also emphasize the critical need for longitudinal follow up of patient care that involved precision medicine along with tumor intrinsic and extrinsic approaches. We need to evaluate the association of precision medicine with clinical outcomes and appreciate the benefits in a more systematic fashion. For example, evaluating
At Nationwide Children’s Hospital however, we are at the forefront of next generation clinical care in Pediatric Neuro-Oncology in our Journey to Best Outcomes. Given the seamless integration of genomic medicine as an addition to the standard of care in our Pediatric Neuro-Oncology service, we are starting to appreciate the important implications of precision medicine and genomics-based approaches to complex disease entities.
each tumor board meeting. Of note, the sequencing results are returned in a timely fashion so the data can be incorporated into clinical decision making and this is just one aspect of our program at Nationwide Children’s that is exemplary. Overall, this multi-disciplinary approach brings together a broad range of expertise to answer challenging clinical questions and design novel treatment strategies based on targeted therapies. There is value in also understanding that the overarching concept of precision medicine is evolving. While the initial emphasis has primarily focused on defining tumor intrinsic driver mutations, there is a growing body of data that suggests that the tumor microenvironment and extrinsic factors including infiltrating immune cells play a role in facilitating cancer progression. To that end, the growing field of immunogenomics within precision medicine is defining mechanisms by which innate and adaptive immune cells play a critical role in promote angiogenesis, invasion and chemotherapy resistance and treatment response. Furthermore, various studies in solid tumors have associated innate immune myeloid cells and tumor associated macrophages as indicators of poor prognosis in addition to their role in T-cell exhaustion
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the standard of care approaches as a control arm in comparison to precision medicine protocols will serve as a method to evaluate outcomes with respect to utilized techniques. We must also continue to develop electronic medical record (EMR) capture tools in order to evaluate clinical parameters (radiographic and histologic) along with laboratory and basic research findings. While the last few years have seen an increase in clinical sequencing studies in pediatric oncology, we still need to evaluate the impact longitudinally on patient care and outcomes. Various precision oncology basket trials also have shown preliminary progress but need further evaluation in refractory or relapsed cancers. Ultimately, a collective analysis of clinical and laboratory research data in conjunction with genomic findings will accelerate better opportunities for precision medicine in children diagnosed with cancer. Overall, our goal in the field of pediatric neuro-oncology is to improve the outcomes of these complex disease entities leveraging precision medicine so we leave a meaningful impact on patients and their families.
Pharmacogenetics and the Controversy on Medication Choices Susan Colace, MD, MSCI Assistant Professor of Pediatrics Co-Director for the Program in Personalized Medicine and Pharmacogenomics Pediatric Hematology/Oncology/BMT
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ost medications we use to treat childhood diseases are chosen based on a variety of factors: the type of disease, whether the patient has any allergies, whether the drug comes in liquid or tablet form, the experience of the health care provider with that medication and so on. Once the medication is chosen, we typically calculate a dose based on the child’s weight and height and we may even adjust the dose by measuring drug levels. Usually, this time-tested method works well, and the chosen medicine works at the prescribed dose. For some patients and some diseases, however, this process is far more challenging. Patients may try medication after medication, only to find that one medication has terrible side effects, and another doesn’t work at all. Another patient may have multiple drug levels drawn over weeks and months, never quite able to find the dose that works for them. Patients, families and providers all end up frustrated and discouraged that a medication simply isn’t working the way it is supposed to, and may start to wonder: is there a better way to do this? Pharmacogenomics is the study of how our genes interact with medications, also known as drug-gene interactions. Our genes are like an instruction manual for our whole body. That includes instructions on how our bodies process medications. Some genes control how medications are absorbed, broken down and removed from the body, while others control how medications are moved around the body to the places they need to go. Small changes in these genes, called genetic variants, can cause two people to process the same medication very differently. They may be the same size, and have the same disease, but need very different doses or respond very differently because of differences in their genes.
the way they are processed in the body. Therefore, not every patient will benefit from genetic testing for selection or dosing of medications. Genetic testing is beneficial for those who are going to be taking medications that have a known, actionable, drug-gene interaction. One misconception regarding pharmacogenomic testing is that it will allow the provider to choose the best medication for the patient. Pharmacogenomic testing cannot identify an individual medication as the best choice for a patient. Rather, it identifies whether there are medications that a patient is less likely to respond to, more likely to have side effects from or more likely to have trouble finding the right dose. The other challenge with pharmacogenomic testing is finding the right time to test for variants in genes that might affect medication choice or dosing. Most pharmacogenomic testing takes several weeks to get results. For patients who need to start a drug very quickly, it can be difficult to have results back in time to be useful. Once a patient has started a medication, pharmacogenomic testing is less useful, as the patient will have already experienced side effects or a need for dose adjustment. Therefore, the best time to perform pharmacogenomic testing is before a patient starts any medications for a particular disease or problem.
There are currently multiple commercial tests available that test for variants in a large number of pharmacogenes, some of which can even be ordered for testing at home, without a health care provider. While these can be interesting and sometimes helpful, most of these large panels test for variants which primarily affect drugs used in adults, and often the interpretation of the results is aimed at adults, rather than children. In some We are constantly learning about drug-gene interactions and cases, the interpretation may lead a provider to avoid how they can be useful to patients. Currently, there are more a medication which could be safely tried in a patient, than 375 unique drug-gene pairs in a database frequently thus unnecessarily eliminating a medication choice. updated by the Clinical Pharmacogenetics Implementation Consortium (CPIC). Not every drug-gene pair is actionable. Every patient’s situation is unique, and it can be helpful to discuss options for testing, as well as interpretation An actionable drug-gene pair means that finding a genetic of test results with an expert in pharmacogenomics. variant would change the way a provider prescribes the Experts at Nationwide Children’s Hospital can help drug. Some drug-gene pairs are informative and simply determine whether pharmacogenomic testing would give us a better of understanding of why two individuals be helpful in a particular child’s case or can assist in might respond to the same drug in different ways. Some interpretation of pharmacogenomic testing results. drugs do not have any known genetic variants that affect IN PATIENT CARE | 17
